Cd and Hg have been implicated in the development of human disease. Functional studies on murine and human B cells demonstrate that B lymphocytes are subject to the immunotoxic effects of Cd and Hg. This provides evidence that the immune system is impaired by Cd and Hg exposure. Biochemical studies revealed that exposure of B lymphocytes to Cd causes changes in the second messenger systems involved in triggering B lymphocyte activation. Specifically, the kinetics and extent of receptor-mediated tyrosine phosphorylation were altered by Cd exposure. Such evidence provides a biochemical basis for Cd immunotoxicity. Experiments are proposed to identify the specific substrates whose phosphorylation is altered by Cd exposure and to determine if Cd directly enhances tyrosine kinase activity in activated B cells. The intention of these studies is to identify Cd-sensitive signalling events in B cells. Triggering B cells with anti-Ig vs anti-CD40 represent polyclonal models of T-independent (TI) vs T-dependent (TD) B cell activation, respectively. Striking differences in the Cd vs Hg sensitivity of anti- CD40-triggered human B cells have been revealed. The activation of B cells triggered with anti-CD40 is sensitive to Hg, yet resistant to Cd inhibition. These overt differences in metal sensitivities will b exploited to find biochemical pathways that are Cd-resistant, yet Hg- sensitive. These Hg-sensitive pathways will be studied in-depth. Such approaches will allow us to focus on signals emanating from the CD40 receptor that are susceptible to immunoregulation by Hg. The differentiation of B cells to produce specific isotypes of Ig is inhibited by low concentrations of Cd and Hg. Studies are proposed to determine the molecular basis for the selective reduction in the expression of specific Ig isotypes by Cd and Hg. It is hypothesized that Cd and Hg may selectively down-regulate the transcription of specific heavy chain genes. If this is the case, the studies would provide an ideal model system to unravel the molecular basis of heavy metal toxicity on gene expression. Even though Cd and Hg exert profound immunosuppressive effects, both of these metals have been implicated in the development of autoimmunity. A hypothesis is presented that proposes that Hg and Cd induce autoimmunity because of their ability to induce metallothionein, heat- shock proteins (Hsp) and other evolutionarily-conserved proteins. T cells reactive to Hsp and other self proteins have been identified in disease states. Given the capacity of metals to induce a plethora of evolutionarily conserved proteins, we propose that these proteins can be processed and presented to auto-reactive T cells and mediate the development of autoimmunity. Strategies to readily test this hypothesis are presented.